Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel

Kaiqian Wang, Christian Holt, Jocelyn Lu, Malene Brohus, Kamilla Taunsig Larsen, Michael Toft Overgaard, Reinhard Wimmer*, Filip Van Petegem

*Corresponding author

Research output: Contribution to journalJournal articleResearchpeer-review

9 Citations (Scopus)

Abstract

Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the CALM genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (CaV1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the CaV1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca2+ by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca2+-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca2+-dependent inactivation of the voltage-gated calcium channel.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number45
Pages (from-to)E10556-E10565
Number of pages10
ISSN0027-8424
DOIs
Publication statusPublished - 6 Nov 2018

Keywords

  • Calcium channels
  • Calcium signaling
  • Inactivation
  • NMR
  • X-ray crystallography

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